The Guidebook Nutritional Anemia

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The Guidebook

Nutritional Anemia

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SIGHT AND LIFE

Press

Edited by

Jane Badham

JB Consultancy, Johannesburg, South Africa

Michael B. Zimmermann

Swiss Federal Institute of Technology, Zurich, Switzerland

Klaus Kraemer

SIGHT AND LIFE, Basel, Switzerland

The Guidebook

Nutritional

Anemia

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SIGHT AND LIFE Mission Statement

SIGHT AND LIFE is a humanitarian initiative of DSM. It aims to ensure a sustainable and significant improvement in human nutrition and health by encouraging partnerships with universities and intergovernmental and governmental agencies, by generating and exchanging scientific information and by forming lasting networks.

SIGHT AND LIFE Press

c/o SIGHT AND LIFE / DSM Nutritional Products Ltd PO Box 2116 4002 Basel Switzerland Phone: +41 61 68 87494 Fax: +41 61 68 81910 Email: [email protected] Internet: www.sightandlife.org

Requests for permission to reproduce or translate SIGHT AND LIFE publications should be submitted to the address above.

Opinions, compilations, tables and figures contained in this publication do not necessarily represent the point of view of SIGHT AND LIFE and are the sole responsibility of the authors. The mention of specific companies and trademarks does not imply that they are endorsed by SIGHT AND LIFE. All reasonable precautions have been taken by SIGHT AND LIFE to verify the content of this publication. However, this publication does not constitute or provide scientific or medical advice and is distributed without warranty of any kind, either express or implied. The reader shall be solely responsible for any interpretation or use of the material contained herein. In no event shall SIGHT AND LIFE be liable for any damages arising from the reader's reliance upon, or use of, these materials.

The paper used in this book is acid-free and falls within the guidelines established to ensure permanence and durability.

Cover photo by Ulla Lohmann, Germany

Cover illustration by graphic art studio, Grenzach-Wyhlen, Germany Typeset and print by Burger Druck, Waldkirch, Germany

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PREFACE TO THE NUTRITIONAL ANEMIA GUIDEBOOK

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Preface

Two hundred million children under the age of five, mostly living in sub-Saharan Africa and South Asia, fail to reach their full cognitive, motor and social-emotional potential because of micronutrient deficiencies and in-adequate stimulation. These children will probably fail at school, fail to achieve their income potential, and remain trapped in the poverty cycle. A tragic reality.

In May 2002, the General Assembly of the United Nations re-emphasized that control of nutritional anemia should be one of the global development goals to be achieved in the early years of this new millennium. Sadly, there has been little documented progress in the global fight against anemia and WHO data shows that 818 million children under the age of five and women are affected by this public health problem, mainly in devel-oping countries. About one million of them die every year. This shows the magnitude of the problem and high-lights the urgent need for action.

SIGHT AND LIFE has always championed interventions to address micronutrient malnutrition, including iron deficiency and nutritional anemias, and, as a result, has published a book, Nutritional Anemia. In a single vol-ume it highlights for the first time all the critical factors in addressing nutritional anemia, with contributions from leading scientists in their respective fields. Each chapter addresses a specific issue in great detail. It has become clear that the effective control of anemia requires inte-grated solutions that are tailored to the particular needs and opportunities in each country. Components of any such an approach include micronutrient supplementation of the most vulnerable groups (particularly children and

women of childbearing age), food fortification, dietary diversification and education, as well as control of dis-eases such as malaria, worm infections, and other chronic endemic infections. While each of these can help reduce the burden of anemia, none is capable of doing the job on its own.

The purpose of this Guidebook is to give you, the reader, a comprehensive summary of the critical issues from prevalence data and statistics, to economics, through to the diagnosis, functional consequences and background information on each of the micronutrients believed to be directly or indirectly involved in anemia.

This Guidebook does not contain all the information or give all the answers, but its intention is to give an over-view of the latest scientific thinking and the challenges facing the world as we go forward in planning, imple-menting and monitoring interventions to address what is undoubtedly the biggest nutritional problem that the world currently faces.

We trust that the information, knowledge and insights that you will gain from this Guidebook, will enable you to become a part of the solution and actively engage in advocacy, programming or on-going research to make a difference.

Jane Badham

Michael B. Zimmermann Klaus Kraemer

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6 _Editors

ABOUT THE EDITORS

JANEBADHAM

Jane is a dietitian with an MSc in Nutrition from North West University, Potchefstroom Campus, South Africa. She is currently the Managing Director of JB Con-sultancy, a health communication and strategy company that advises the pharmaceutical industry, food industry, humanitarian organizations, and the media. Jane is also the CEO of the 5-a-Day for Better Health TRUST in South Africa that promotes the increased consumption of vegetables and fruit. She serves on the Board of Directors of the International Fruit and Vegetable Alliance (IFAVA) as well as being part of the organizing team of the African Nutrition Leadership Program (ANLP).

MICHAELZIMMERMANN

Michael obtained his MD from Vanderbilt University School of Medicine and his MSc in Nutritional Science at the University of California in Berkeley, both in the USA. He is currently Senior Scientist in the Laboratory for Human Nutrition at the Swiss Federal Institute of Technology in Zurich (ETH), visiting Professor at Wageningen University in the Netherlands, and holds the Unilever Endowed Chair in International Health and Micronutrients. Michael’s research focus is nutrition and metabolism, including the effects of micronutrient defi-ciencies on thyroid function, and he has won many awards for his work.

KLAUSKRAEMER

Klaus obtained his doctorate in nutritional sciences from the University of Giessen, Germany. He is currently Secretary General of SIGHT AND LIFE, a humanitarian initiative of DSM, involved in a number of activities to ensure a sustainable and significant improvement in human nutrition, health, and wellbeing. Klaus has over 20 years of research experience in the field of health and safety of vitamins, minerals, carote-noids, and nutraceuticals. He serves on several profes-sional societies dedicated to nutrition, vitamins, and anti-oxidants, has published many scientific articles, and coedited five books.

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Contributors

HAROLDALDERMAN

Africa Region of the World Bank, Washington, DC, USA; [email protected]

JANEBADHAM

JB Consultancy, Health Communication and Strategy Consultants, Johannesburg, South Africa;

[email protected]

HANS-KONRADBIESALSKI

Institute for Biological Chemistry and Nutrition at the University of Hohenheim, Hohenheim, Germany; [email protected]

MARTINBLOEM

World Food Programme (WFP), Rome, Italy; [email protected]

TOMMASOCAVALLI-SFORZA

Nutrition and Food Safety, WHO Regional Office for the Western Pacific, Manila, Philippines;

[email protected]

MARYCOGSWELL

Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention, Atlanta; USA

IANDARNTON-HILL

Nutrition Section, UNICEF, New York, USA; [email protected]

OMARDARY

A2Z Project, Academy for Educational Development, Washington, DC, USA; [email protected]

BRUNO DEBENOIST

World Health Organization (WHO), Geneva, Switzer-land; [email protected]

SASKIA DEPEE

World Food Programme (WFP), Rome, Italy; [email protected]

INESEGLI

Institute of Food Science and Nutrition, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland; [email protected]

JÜRGENERHARDT

University of Indonesia, SEAMEO-TROPMED, Jakarta, Indonesia; [email protected]

ALISOND. GERNAND

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, USA; [email protected]

GARYR. GLEASON

Friedman School of Nutrition Science and Policy, Tufts University, Boston, USA;

[email protected]

EVAHERTRAMPFDÍAZ

Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile; [email protected]

SUSANHORTON

Wilfrid Laurier University, Waterloo, Canada; [email protected]

RICHARDHURRELL

Institute of Food Science and Nutrition, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland; [email protected]

ALANJACKSON

Institute of Human Nutrition, University of Southamp-ton, SouthampSouthamp-ton, UK; [email protected]

AFAFKAMAL-ELDIN

Department of Food Science, Swedish University of Agricultural Sciences, Uppsala, Sweden;

[email protected]

KLAUSKRAEMER

SIGHT AND LIFE, Basel, Switzerland; [email protected]

SEANLYNCH

Eastern Virginia Medical School, Norfolk, USA; [email protected]

M.G. VENKATESHMANNAR

The Micronutrient Initiative, Ottawa, Canada; [email protected]

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8 _Contributors

ERINMCLEAN

World Health Organization (WHO), Geneva, Switzer-land; [email protected]

REGINAMOENCH-PFANNER

Global Alliance for Improved Nutrition (GAIN), Geneva, Switzerland; [email protected]

CHRISTINEA. NORTHROP-CLEWES

Northern Ireland Centre for Food and Health, University of Ulster, Coleraine, UK; [email protected]

MANUELOLIVARES

Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile; [email protected]

NEALPARAGAS

Institute of Human Nutrition, Columbia University, New York, USA; [email protected]

KLAUSSCHÜMANN

Technical University of Munich, Freising, Germany; [email protected]

JOHNM. SCOTT

School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland; [email protected]

NEVINSCRIMSHAW

International Nutrition Foundation, Boston, USA; [email protected]

RICHARDSEMBA

School of Medicine, Johns Hopkins University, Baltimore, USA; [email protected]

NOELSOLOMONS

Center for Studies of Sensory Impairment, Aging and Metabolism (CeSSIAM), Guatemala City, Guatemala; [email protected]

ALFREDSOMMER

ELISABETHSTOECKLIN

R & D Human Nutrition and Health, DSM Nutritional Products Ltd, Kaiseraugst, Switzerland;

[email protected]

BRIANTHOMPSON

Food and Agriculture Organization (FAO), Rome, Italy; [email protected]

DAVIDTHURNHAM

Northern Ireland Centre for Food and Health, University of Ulster, Coleraine, UK;

[email protected]

MELODYC. TONDEUR

Division of Gastroenterology, Hepatology and Nutri-tion, Hospital for Sick Children, Toronto, Canada, [email protected]

MARETG. TRABER

Linus Pauling Institute & Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, USA; [email protected]

RICARDOUAUY

Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile;

[email protected]

KEITHP. WEST

DANIELWOJDYLA

Escuela de Estadistica, Universidad Nacional de Rosario, Argentina

MICHAELZIMMERMANN

Laboratory for Human Nutrition, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland; [email protected]

STANLEYZLOTKIN

Departments of Paediatrics and Nutritional Sciences and Public Health Sciences, University of Toronto, Canada; [email protected]

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Contents

Preface 5

About the editors 6

Contributors 7

Contents 9

CHAPTER 1 Worldwide prevalence of anemia in preschool aged children, pregnant women and non-pregnant women of reproductive age

Erin McLean, Ines Egli, Mary Cogswell, Bruno de Benoist

and Daniel Wojdyla 11

CHAPTER 2 The case for urgent action to address nutritional anemia

M.G. Venkatesh Mannar 12

CHAPTER 3 The economics of addressing nutritional anemia

Harold Alderman and Susan Horton 13

CHAPTER 4 Diagnosis of nutritional anemia – laboratory assessment of iron status

Hans-Konrad Biesalski and Jürgen G. Erhardt 15

CHAPTER 5 An overview of the functional significance of iron deficiency

Gary Gleason and Nevin S. Scrimshaw 16

CHAPTER 6 Iron metabolism

Sean Lynch 17

CHAPTER 7 Optimizing the bioavailability of iron compounds for food fortification

Richard Hurrell and Ines Egli 19

CHAPTER 8 Copper and zinc interactions in anemia: a public health perspective

Manuel Olivares and Eva Hertrampf and Ricardo Uauy 21

CHAPTER 9 Nutritional anemia: B-vitamins

John M. Scott 22

CHAPTER 10 Vitamin A in nutritional anemia

Keith P. West, Jr., Alison D. Gernand and Alfred Sommer 24

CHAPTER 11 Oxidative stress and vitamin E in anemia

Maret G. Traber and Afaf Kamal-Eldin 26

CHAPTER 12 Selenium

Richard D. Semba 27

CHAPTER 13 Interactions between iron and vitamin A, riboflavin, copper, and zinc in the etiology of anemia

Michael B. Zimmermann 28

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CHAPTER 14 Anemia in severe undernutrition (malnutrition)

Alan A. Jackson 29

CHAPTER 15 Infection and the etiology of anemia

David I. Thurnham and Christine A. Northrop-Clewes 31

CHAPTER 16 Making programs for controlling anemia more successful

Saskia de Pee, Martin W. Bloem, Regina Moench-Pfanner

and Richard D. Semba 33

CHAPTER 17 Successful approaches: Sprinkles

Stanley H. Zlotkin and Melody Tondeur 36

CHAPTER 18 Safety of interventions to reduce nutritional anemias

Klaus Schümann and Noel W. Solomons 37

CHAPTER 19 The importance and limitations of food fortification for the management of nutritional anemias

Omar Dary 42

CHAPTER 20 Food-based approaches for combating iron deficiency

Brian Thompson 43

CHAPTER 21 Global perspectives: accelerating progress on preventing

and controlling nutritional anemia

Ian Darnton-Hill, Neal Paragas and Tommaso Cavalli-Sforza 45

CHAPTER 22 Conclusions and research agenda

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1 · Worldwide prevalence of anemia

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WORLDWIDE PREVALENCE OF ANEMIA IN PRESCHOOL AGED CHILDREN, PREGNANT WOMEN AND NON-PREGNANT WOMEN OF

REPRODUCTIVE AGE

Erin McLean, Mary Cogswell, Ines Egli, Daniel Wojdyla and Bruno de Benoist

What is the problem and what do we know so far?

Anemia is a widespread public health problem associated with an increased risk of morbidity and mortality, espe-cially in pregnant women and young children. It is a disease with multiple causes, both nutritional (vitamin and mineral deficiencies) and non-nutritional (infection) that frequently co-occur. It is assumed that one of the most common con-tributing factors is iron deficiency, and anemia resulting from iron deficiency is considered to be one of the top ten contributors to the global burden of disease.

The World Health Organization (WHO) has as one of its mandates to inform its Member States about the global health situation. It was decided to update the global esti-mates of anemia and provide a current picture of the situ-ation, especially in high-risk groups. This was done by generating global and United Nations Regional estimates of anemia prevalence in preschool aged children, preg-nant women and non-pregpreg-nant women of childbearing age. Data was gathered between 1993 and 2005, using the most recent nationally representative survey for a country or from at least two surveys representative of the countries first administrative boundary. When data was not available for a country, the anemia prevalence was predicted based on regression equations using the coun-try’s United Nations Human Development Index and health indicators from the World Health Statistics data-base. Coverage varied by UN Regions and was highest in northern America, Asia and Africa while it was lower in Europe and Oceania. The estimates are based on the 192 Member States of WHO, so represent 99.8% of the global population.

What do we know about global prevalence of anemia?

• Global prevalence of anemia in preschool aged children is 47.4%.

• Global prevalence of anemia in pregnant women is 41.8%.

• Global prevalence of anemia in non-pregnant women is 30.2%.

• Globally 818 million women (both pregnant and non-pregnant) and young children suffer from anemia and over half of these, approximately 520 million, live in Asia.

• The highest prevalence for all 3 groups is in Africa, but the greatest number of people affected are in Asia. • In Asia 58% of preschool aged children, 56.1% of pregnant women and 68% of non-pregnant women are anemic.

• More than half of the world’s population of preschool aged children and pregnant women reside in countries where anemia is a severe public health problem. • Countries with a severe public health problem were

grouped in Africa, Asia and Latin America and the Caribbean.

• Africa and Asia are the most affected and as these regions are also the poorest, it may reflect the link between anemia and development.

• Compared to North America, anemia is three times more prevalent in Europe and this may be due to the fact that Europe includes countries with a range of social and economic profiles or as a result of low cover-age of data in Europe compared to North America or that in north America foods are widely fortified with iron and a high proportion of iron intake comes from fortified foods.

It has to be noted that these estimates are not quantita-tively comparable to previous estimates as the method-ologies used are different. They do have some limitations but, based on the best available information, they are a good starting point to track progress in the elimination of anemia.

Based on these estimates, the magnitude of nutritional anemia or of iron deficiency anemia is difficult to assess since most of the surveys used do not address the causes of anemia and are solely restricted to the measurement of hemoglobin.

What is the way forward?

Globally, almost half of all preschool aged children and pregnant women and close to one third of non-pregnant women, suffer from anemia. As the estimates represent a large segment of the population, they are likely to reflect the actual global prevalence of anemia within these popu-lation groups. However, UN Regional estimates may be more accurate for some populations and some areas since the coverage varies significantly within regions.

Anemia is of greatest concern in children less than 2years of age since their rapid growth requires a high

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12 _{2 · The case for urgent action to address nutritional anemia}

intake of iron, which frequently is not covered by the diet, especially in low-income countries.

In order to make full use of these prevalence data, infor-mation on the cause of anemia should be collected in any survey on anemia so that interventions for anemia control can be better adapted to the local situation and therefore be more effective.

What is the key message?

Anemia remains a significant public health concern. These new estimates are likely to reflect the current situ-ation and are a good starting point for tracking global progress. Future surveys need to include data on the causes of anemia, as lack of this data impairs our ability to correct this significant public health problem.

FACTS:

• Preschool children are aged between 0–4.99 years, non-pregnant women between 15 and 49.99 years and no age defined for pregnant women.

• Hemoglobin concentration cut-offs to define anemia as set by the WHO are 110 g/L for pre-school aged children and pregnant women, and 120 g/L for non-pregnant women.

• The prevalence of anemia as a public health problem is categorized by the WHO as follows:

• <5% – no problem

• 5–19% – mild public health problem • 20–39% – moderate public health problem • >40% – severe public health problem

• Global prevalence of anemia in preschool aged children is 47.4%

• Global prevalence of anemia in pregnant women is 41.8%

• Global prevalence of anemia in non-pregnant women is 30.2%

• Globally 818 million women (both pregnant and non-pregnant) and young children suffer from anemia and over half of these, approximately 520 million, live in Asia.

• The highest prevalence for all 3 groups is in Africa, but the greatest number of people affected are in Asia. • In Asia 58% of preschool aged children, 56.1% of pregnant women and 68% of non-pregnant women are anemic.

• More than half of the world’s population of preschool aged children and pregnant women reside in countries where anemia is a severe public health problem. • Countries with a severe public health problem were

grouped in Africa, Asia and Latin America and the Caribbean.

• Africa and Asia are the most affected and as these regions are also the poorest, it may reflect the link between anemia and development.

• Compared to North America, anemia is three times more prevalent in Europe.

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THE CASE FOR URGENT ACTION TO ADDRESS NUTRITIONAL ANEMIA

Venkatesh Mannar

The United Nations goal of reducing by one third the prevalence of anemia by 2010 is unlikely to be met. Nutritional anemia remains common in many countries of the world and its eradication through effective inter-ventions must be a priority for attention and action. Iron deficiency in early childhood has a significant, negative effect on a child’s physical and intellectual development. There has been an intensification of efforts in several countries and this gives encouragement that interven-tions can be successful and sustainable. It is recognized, however, that there are no easy solutions and effective interventions have their drawbacks, but it would seem that lack of priority of eradicating nutritional anemia by policy makers is the major concern. There is an urgency to act.

What has been achieved?

There are key developments that have occurred in the past 10 years:

• More technical consensus

• Better understanding of conditions needed for effec-tive supplementation

• Sufficient knowledge and experience (especially with pregnant women) to design and implement effective programs

• Programmatic and technical guidelines for effective programming

• Better information on stable and bioavailable iron compounds

• Recognition by the food industry of the need for for-tification

• Feasibility of double salt fortification

• Technology to fortify rice with iron and folic acid • Increased successful work relating to improved

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• Greater knowledge about the interface between iron status and infection.

Concerns are that although iron supplementation has been shown to be effective in controlled experiments, supplementation in field settings does not seem to show a significant improvement in anemia prevalence. In addition, data to support large-scale food fortifica-tion is still lacking and has not been systematically documented.

It seems that progress will only be made if:

1. Key issues are addressed and consensus statements developed

2. Bridges are built between science/technology and those who deliver the services

3. The field application of supplementation is strength-ened

4. Universal fortification of staple foods with significant levels of nutrients is globally recognized

5. Creative means of increasing the iron content of the diet are explored

6. Enhancing the iron absorption from diets is investigated 7. There is a better understanding of interactions be-tween micronutrients and other dietary components and other causes of anemia

8. Social marketing and supporting behavioral change is encouraged

9. There is a combination of proper regulation and strong and appropriate public education

10. A multi-intervention approach is accepted that in-cludes adequate nutritional intake (supplementation, fortification, dietary modification, biofortification) and reduction of concurrent infection

11. There is more compelling advocacy at all levels, forming of strategic alliances and commitment to action

12. There are global champions to push action forward.

There is an urgent need for action but that action needs to consider a number of factors if it is to be successful and sustainable.

FACTS:

• Iron deficiency could be preventing 40%-60% of children in developing countries from growing to their full mental potential.

• The WHO identifies iron deficiency as being amongst the ten most serious risks in countries with a high infant mortality coupled with a high adult mortality.

• Interventions to address iron deficiency are one of the most cost effective public health interventions. • The cost-benefits ratio for iron programs is estimated

to be 200:1.

• Amongst a list of 17 possible development invest-ments, the returns of investing in micronutrient programs are second only to those of fighting HIV/AIDS.

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THE ECONOMICS OF ADDRESSING NUTRITIONAL ANEMIA

Harold Alderman and Susan Horton

Why is economic assessment important?

The economic gains from addressing any micronutrient deficiency come from both cost reductions and from enhanced productivity. They include lower mortality, reduced healthcare costs, reduced morbidity, improved productivity and intergenerational benefits through improved health. In the case of iron deficiency anemia, economic assessment requires determining the costs of iron deficiency in dollar terms in order to determine the consequences in a unit of measurement that is common to other claims on public resources (both health interven-tions and interveninterven-tions outside the health arena). This is in partial contrast to the calculation of a program’s effectiveness in terms of increases in life expectancy or disability-adjusted life years (DALYs).

It is also important to assess the economic impact of interventions in terms of cost and benefits. In making economic assessments, there are a number of important issues that must be considered:

• There may be more than a single outcome for the intervention (e.g. an intervention in pregnant women may both reduce low birth weights and maternal mortality via changes in maternal hemoglobin); • Some interventions affect not only anemia but also

other health and economic outcomes (e.g. deworm-ing can be effective in both improvdeworm-ing hemoglobin levels as well as absorption of vitamin A);

• Measuring cost-effectiveness using the ultimate out-come of interest (e.g. mortality) is usually too costly and time consuming and so often only proximate indicators (e.g. proportion anemic or hemoglobin) are used;

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14 _{3 · The economics of addressing nutritional anemia}

• Cost-effectiveness varies with the scale of the pro-gram (e.g. costs may decrease over time if there are fixed costs that can be spread over larger pro-grams);

• There are distinctions between public and private costs (e.g. the cost of a dollar of government revenues is generally more than a dollar to the economy).

How are the economic benefits of addressing anemia assessed?

There are two key approaches that are used:

1. Calculation of the expected gains in economic terms if a case of anemia were prevented. This approach is useful for making comparisons of intervention costs. 2. Estimation of the impact on GNP if anemia rates could be reduced. This approach scales the individual gains and results in a stronger motivation for a change in political will.

Results of economic benefits can either be reported in costs in terms of productivity; give sensitivity estimates; or be reported in terms of DALYs, which are then con-verted into dollar terms.

Each approach has its advantages and limitations. It is important to recognize that placing precise figures on economic value involves a range of assumptions and requires the adaptation to a country’s specific context. These approaches all measure different concepts and so cannot be directly compared.

What are the economic costs of reducing anemia?

In terms of either the cost per DALY saved, or the cost-benefit ratio calculated, iron fortification is one of the most attractive public health interventions available. • The cost of fortification per person per year is in the

range of $0.10 (US) to $1.00.

• Home fortification is relatively new and holds con-siderable promise for some groups and the costs can be viewed as intermediate between fortification and supplementation.

• Supplementation costs per person are estimated in the range of $2.00–$5.00, noting, however, that often reported costs do not fully cover personnel costs and that results of programs at scale have been disappointing. Operational research is needed to design programs which work cost-effectively in the field.

• Periodic deworming has been estimated in one study to cost US$3.50 to increase school participation by one child year. A combined program of deworming and supplementation, using a number of

assump-tions, estimated that the intervention could lead to an expected additional income of $29 for a cost of $1.70. Deworming has possibly been overlooked in importance and works synergistically with fortifi-cation and supplementation.

• There are few studies that have shown the cost-effec-tiveness of home gardening and increased production of small animals.

• Biofortification approaches are promising but involve extensive fixed costs for research, but with few, if any, incremental costs of operation over the general costs of producing a crop with increased iron availability. Using a number of assumptions, the strategy could provide global total present value of nutritional benefits of up to $694 million, giving a cost-benefit ratio of 19 or an internal return of 29%.

What are the outcomes of economic assessments that have been undertaken?

It is clear (see FACTS below) that anemia at all stages of the lifecycle is associated with a significant health burden and has a potentially large negative impact on productivity and hence also on income and GDP. The total loss per capi-ta due to physical as well as cognitive losses, amounts to billions annually and is considerable when compared to the modest costs of decreasing nutritional anemia.

Economic impact studies show that addressing nutritional anemia can have a significant impact on health burden, productivity and income. Determining the overall eco-nomic impact (ecoeco-nomic gain and cost-effectiveness) of any intervention requires expert knowledge and must be based on the specifics of the program, the country and the desired outcome measurements.

FACTS:

• One study estimates that in developing countries one fifth of perinatal mortality, and one tenth of maternal mortality, is attributable to iron deficiency.

• It is estimated that 1.5% of deaths worldwide are attributable to iron deficiency.

• In terms of DALYs, anemia also accounts for 35 million health life years lost (2.5% of global DALYs lost). • Iron interventions in adults have shown increased

productivity by around 5% in light manual labor and as high as 17% in heavy manual labor.

• An Indonesian study shows effects on income of the self employed of as much as 20% for men and 6% for women.

• A range of studies indicate that a half standard deviation change in IQ impacts on earnings in the region of 5%.

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4 · Diagnosis of nutritional anemia

• It can be inferred that due to its effects on cognitive development, anemia potentially reduces adult earn-ings by 2.5%.

• The cost of fortification per person per year is in the range of $0.10 (US) to $1.00, with a cost-benefit ratio of between 6:1 (physical benefits to adults) and 9:1 (including estimated cognitive benefits to children). • Supplementation costs per person are estimated in the

range of $2.00 to $5.00, noting that often these costs do not fully cover personnel costs.

• Supplementation programs are 5 times more costly than fortification in per DALY terms.

• Deworming has been estimated in one study to cost $3.50 to increase school participation by one child year. • A combined programs of deworming and

supplemen-tation is estimated to impact on earnings, with an additional $29.00 expected for a cost of $1.70.

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LABORATORY ASSESSMENT OF IRON STATUS

Hans-Konrad Biesalski and Jürgen Erhardt

Nutrition has a important role in anemia and of all the nutrients involved, iron is the most crucial. Therefore the assessment of the iron status is very often essential in the diagnosis of anemia. Iron deficiency generally occurs in three sequential stages: depleted iron stores, iron defi-cient erythropoesis and iron deficiency anemia. All three stages can be analyzed biochemically with the measure-ment of hemoglobin (Hb), ferritin and soluble transferrin receptor (sTfR). Although there are some clinical indica-tors and the evaluation of iron intake might be helpful, the diagnosis relies mainly on these biochemical indica-tors. They are the only ones which give the necessary specificity and sensitivity. Unfortunately the procedures to measure them are costly and mostly not easy to per-form.

How accurate and useful are the different biochemical indicators?

To measure the iron status there are three important indi-cators:

1. Hb: The measurement of Hb is essential for the diag-nosis of nutritional anemia and is one of the most common, easiest and least expensive methods. Kits are available from several manufacturers and there

are also small portable hemoglobinometers for use in the field. Unfortunately the Hb measurement is not very sensitive and specific for iron deficiency (only the third stage affects Hb synthesis). Thus, to deter-mine if iron deficiency is responsible for anemia, it is usually necessary to include other indicators. 2. Ferritin: It is currently considered the most important

indicator of the iron status as even in the first stage of iron deficiency, its concentration decreases. There-fore it is the most sensitive indicator and the cost of ferritin ELISA kits or other methods for the measure-ment of ferritin are relatively low. It is important to note that ferritin is increased by many factors, includ-ing infection and inflammation, thus a high value does not necessarily indicate a good iron status. It is therefore also valuable to measure parameters for acute [c-reactive protein (CRP)] and chronic infec-tion [alpha-1-glycoprotein (AGP)].

3. Soluble Transferrin Receptor (sTfR). The measure-ment of this indicator is increasingly being used to determine iron deficiency in situations where infec-tion is a factor, as it is much less influenced by this condition. It is not as sensitive as ferritin, but more sensitive than Hb. Until now there is no internation-ally certified standard available and each method/kit has its own cut off values. sTfR measurements are still much more expensive than ferritin measure-ments. The ratio of sTfR to ferritin is the most sensi-tive indicator for the iron status, since it allows the calculation of the iron stores in mg/kg body weight. It is therefore similar to the gold standard of bone marrow staining in defining iron deficiency.

Besides these indicators the following three are some-times also of interest:

1. Iron saturation of plasma transferrin and mean cor-puscular volume (MCV): They are well established indicators and relatively inexpensive to measure but only useful in clinical settings where the equipment to measure them is available.

2. Hematocrit: Is very easy to measure but since it is even less sensitive than Hb for iron deficiency it is not very helpful in diagnosing nutritional anemia. 3. Zinc protoporphyrin (ZnPP): It is a simple and robust

measurement and useful in screening for iron deficien-cy but requires a special machine. It must be noted that lead even at normal environmental exposures can increase ZnPP. In most situations, though, it is not a problem.

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16 _{5 · The functional significance of iron deficiency anemia}

sTfR and parameters of infection (CRP, AGP) are the best indicators to measure iron status, but four key ele-ments need to be improved through on-going research: reduction of costs; improvement of throughput; increase of sensitivity/specificity and increase of robustness.

Another key challenge is to make the collection of blood in the field as easy and reliable as possible. The collec-tion of blood samples on filter paper is an alternative to venous blood samples, since it doesn’t require centri-fugation, freezing or transport of samples in a cold chain. Unfortunately, dried blood spots (DBS) have some limi-tations and requiring strict procedures to be followed.

The combination of Hb, ferritin, sTfR and parameters of infection (CRP, AGP) are the best indicators to measure iron status, but to ensure implementation and accuracy of interventions, especially in developing countries, there needs to be more research in reducing the cost, improv-ing the robustness of the measurements and findimprov-ing easy field methods.

5

AN OVERVIEW OF THE FUNCTIONAL SIGNIFICANCE OF IRON DEFICIENCY ANEMIA

Gary Gleason and Nevin Scrimshaw

Iron deficiency anemia is the most widespread micronutri-ent and overall nutritional deficiency in the world. Iron deficiency occurs in three different stages. The first, deple-tion of iron stores, has no funcdeple-tional changes. When iron stores are exhausted, however, and tissues begin to have insufficient iron, the resulting condition is iron deficiency. Negative effects amongst those who are iron deficient, but do not have outright anemia, include cognitive impairment, decreased physical capacity, and reduced immunity. Thus there are adverse consequences from iron deficiency even before iron deficiency anemia is present. The final stage is iron deficiency anemia which, when severe, can be fatal.

Iron deficiency anemia during pregnancy is prevalent because additional iron is needed to supply the mother’s expanding blood volume (520% increase) and to support the needs of the growing fetus and placenta. Thus, during the second half of pregnancy, although pregnant women

have been shown to absorb more iron from food, even in healthy women the iron requirement cannot be easily met by diet. Anemia in pregnancy is associated with increased maternal and child morbidity and mortality and lower birth weight. Favorable pregnancy outcomes occur 30–45% less often in anemic mothers, and infants of anemic mothers are less likely to have normal iron reserves – so they start life at a disadvantage.

Considerable emphasis is placed on reducing iron anemia in infancy and early childhood because of its association with impaired psychomotor performance as well as changes in behavior. Although some of the developmen-tal deficits can be corrected with iron treatment, newer studies suggest that difference in cognitive and social adaptation remain, and are likely to be permanent. The risk of iron deficiency is high during later infancy and young childhood, because the stores received at birth have been used to support normal functions and growth and only about 50% of the iron requirement of a 6 month old can be obtained from breast milk. Thus continued breastfeeding will supply only half the infant’s iron needs, and for many children the other half (+4 mg/day) must come from fortified complementary foods or sup-plementation if anemia is to be avoided. This is further aggravated in infants who were of low birth weight, which is common when the mother is malnourished dur-ing pregnancy. Hence the WHO and UNICEF recom-mendation that low birth-weight infants in populations with high levels of anemia receive supplementary iron beginning at 2 months and continuing up to 24 months. As children grow older and start school, studies have shown that those who are anemic have poorer perform-ance. This has serious implications for the effectiveness of education, especially in developing countries in which anemia is highly prevalent.

Addressing iron deficiency and iron deficiency anemia from pregnancy through to infancy and childhood is critical, and interventions need to start early in the lifecycle.

Research also shows the impact of iron status on: • Physical capacity – iron deficiency reduces physical

performance and has been especially noted in agri-cultural workers.

• Morbidity from infection due to iron’s role in several biological mechanisms involved in the immune response to infections. There remains some debate and unresolved issues, especially the relationship between iron supplementation of young children who are not iron deficient and malaria. More research is

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17

6 · Iron metabolism

necessary. New recommendations from the WHO are that iron deficiency anemia should be determined in young children in areas where malaria is endemic before they are given iron supplements. There is less controversy with regards to other infections but there are still some cautions. The evidence supports a decreased resistance to infection in iron deficient individuals. However, if they are severely malnour-ished and anemic, the body mechanisms that with-hold iron from pathogens can be overwhelmed by too much iron (particularly administered parenterally). Under these circumstances the pathogen can grow explosively before the immune system can recover from the effects of the iron deficiency with disastrous effects to the individual.

• Temperature regulation – severe iron deficiency low-ers the body’s ability to maintain body temperature in a cold environment.

• Iron excess and chronic disease - concerns have been raised about the possible relationship between high iron stores and heart disease or cancer. Although the studies that have been undertaken are inconclusive, they indicate the need for more research in this field.

In general, the negative effects of iron deficiency on health, physical capacity, work performance, cognitive performance and behavior can be corrected by providing adequate iron. Strategies to assure adequate iron nutrition include a combination of promoting a diverse diet with iron-rich foods, micronutrient fortification of staples and targeted fortification or iron supplementation for groups at high risk or with especially high needs. If moderate to severe iron deficiency anemia occurs in infancy, the effects on cognition may not be reversible. Iron should be viewed as a two edged sword in that either too little or too much can have serious adverse consequence for the individual.

The functional consequences of iron deficiency, and the longer term economic and social impact, has led to a global target to reduce anemia prevalence by 30% from the year 2000 levels by 2010. As of 2007, there has not been substantial progress in most developing countries and iron deficiency anemia should be addressed as a pri-ority, especially in the highest risk groups; pregnant women, infants, and young children. However, there are some areas where caution is needed to avoid a potentially negative impact of interventions.

FACTS:

• In many developing countries one out of two preg-nant women, and more than one out of every three preschool children, are estimated to be anemic. • In countries where meat consumption is low, up to 90%

of women are, or become, anemic during pregnancy. • It is estimated that 800000 deaths worldwide are

attributable to iron deficiency anemia, and it remains amongst the 15 leading contributors to the global bur-den of disease.

• When measured in DALYs, iron deficiency anemia accounts for 25 million or 2.4% of the total DALYs. • A normal male body has in total ₅4.0 g of iron and a

normal woman an average of 2.5 g.

• Approximately 73% of the body’s iron is in hemoglo-bin in circulating red cells and in the muscle protein myoglobin, 12% in iron storage proteins, and another 15% is critically important in dozens of enzymes that are essential for the functioning of all cells and tissues. Below normal hemoglobin levels, physical work capa-city is linearly related to hemoglobin levels. This is particularly significant when hemoglobin concentra-tion falls below 100 g/L, which is 20–40 g/L below the lower limit of normal adults.

• Moderate anemia is defined as hemoglobin of 70– 90 g/L, and severe anemia as hemoglobin of <70 g/L. • Favorable pregnancy outcomes occur 30–45% less

often in anemic mothers, and infants of anemic mothers are less likely to have normal iron reserves.

• The global target is to reduce anemia prevalence nationally, including iron deficiency, by 30% from the year 2000 levels by 2010. Progress as of 2007 was not on pace in most developing countries to meet this goal.

6

IRON METABOLISM

Sean Lynch

What do we know so far?

Iron plays a vital role in oxygen transport and storage, oxidative metabolism, cellular proliferation and many other physiological processes. It has a key property that allows it to co-ordinate electron donors and to participate in redox processes. This property also accounts for its potential to cause toxic effects through the generation of free radicals. Furthermore, iron is an essential nutrient

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18 _{6 · Iron metabolism}

for all known pathogens. Freely available, iron may great-ly increase their virulence. It is therefore not surprising that the human body has tightly regulated processes for absorbing, transporting and storing iron. They ensure that there is a ready supply for cellular growth and func-tion. At the same time they limit its participation in potentially toxic free radical reactions. They also prevent pathogens from getting ready access to the iron.

Approximately 75% of the iron in the body is present in metabolically active compounds. The remaining 25% constitutes a dynamic store that is turned over constantly. This store ensures an adequate supply for normal organ function despite short-term variations in absorption or loss from the body. It also supplies the immediate needs when requirements are increased. The iron reserves that have then been utilized are then gradually replaced by increased absorption. The circulating transferrin pool supplies almost all functional requirements. It contains only about 3 mg iron in adults, but ten times as much (₅35 mg) moves through the pool each day, roughly 80% destined for red blood cell production. Most of the iron that is transferred from the dynamic store to the cir-culating transferrin pool comes from iron recovered from the processing of hemoglobin in red cells that have reached the end of their approximately four month life spans. Absorbed iron also enters this pool, but it amounts to only about 1–1.5 mg a day. The release of iron into the circulation is tightly regulated in concert with requirements. It can be reduced or accelerated several fold. However the saturation of transferrin with iron (the proportion of the protein that is carrying iron at any one time) is held at approximately 35% in normal individu-als with adequate iron reserves.

What recent achievements have improved our understanding of iron metabolism?

The recent discovery of a small cysteine-rich cationic peptide called hepcidin, which is produced in the liver, circulates in the plasma and is excreted in the urine, has revolutionized our understanding of the regulation of iron absorption and storage. Hepcidin appears to have a primary role in ensuring the maintenance of an optimal iron store, in regulating iron delivery to all body cells in concert with their functional requirements and blocking the absorption of unneeded iron through the intestine. It acts as a negative regulator of release from stores and intestinal absorption. High levels reduce the rate of release from stores and absorption from the intestine by binding to the only known cellular iron exporter, ferro-portin, causing it to be degraded. The expression of hep-cidin is induced independently by the accumulation of

storage iron and by inflammation. It is suppressed when iron stores are depleted, and by anemia, hypoxemia and accelerated erythropoiesis. Hepcidin ensures that body tissues receive the right amount of iron to meet their functional needs. However all cells also have the capacity to regulate their own internal iron economy by increas-ing or decreasincreas-ing the expression of transferrin receptors which are required for the uptake of iron from the circu-lating transferrin pool into cells.

It has been known that iron balance is maintained by the control of absorption for a long time. However sig-nificant advances in our understanding of the processes regulating absorption have also taken place recently. Absorption occurs primarily in the proximal small intes-tine through mature enterocytes located at the tips of the duodenal villi. Two transporters, Heme Carrier Protein 1 (HCP1) and Divalent Metal Transporter 1 (DMT1) appear to mediate the entry of most if not all dietary iron into these mucosal cells. Heme iron is always readily absorbed. Intact heme molecules are transported into the enterocytes. However, heme constitutes only a small proportion of dietary iron even for people who eat a lot of meat or fish. Most of the iron is present in other forms referred to collectively as nonheme iron. This iron is transported into the enterocytes by DMT1, but it must first be solubilized and reduced to the ferrous state. Moreover factors in food, particularly phytates and polyphenols, may prevent the binding of nonheme iron to DMT1. As a consequence absorption is inhibited. The possibility that specific receptors for other forms of dietary iron have a significant role in absorption awaits further clarification. As indicated above absorption is regulated by the control of iron export from duodenal enterocytes to the circulating transferrin pool by ferro-portin. These enterocytes have a short lifespan and iron that is not transferred to the circulation is lost when the cells exfoliate. Nonheme iron absorption is also regulated at the stage of entry into the enterocytes by modifications in the expression of DMT1.

What are the iron requirements throughout the human lifecycle?

Iron is found in almost all foods. Dietary iron intake is therefore related to energy intake. Iron requirements are highest in the second and third trimesters of pregnancy. This need is met utilizing the maternal stores accumulated prior to conception and during the first trimester owing to the cessation of menstruation as well as markedly increased absorption during the second and third trimesters. Requirements are also high in young children particularly between 6 and 18 months of age. Once birth

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19

7 · Bioavailability of iron compounds for food fortification

iron reserves are exhausted, infants depend on weaning foods for iron because the iron content of human milk is low. Unfortunately, traditional weaning foods in many developing countries are poor sources of bioavailable iron. Children aged 6 to 18 months are therefore frequently iron deficient. Requirements are increased during the adolescent growth spurt and by the onset of menstruation in girls. Finally women of childbearing age are at risk for iron deficiency because of their menstrual iron losses. Iron requirements are least in men and postmenopausal women.

What disorders of iron balance are found?

The three common disorders of iron balance are iron deficiency, iron overload and the anemia of inflamma-tion (also called the anemia of chronic disease).

1. Iron deficiency remains the most common micronu-trient deficiency disorder worldwide. It is virtually always an acquired condition resulting from a diet that contains insufficient bioavailable iron. In developing countries traditional foods usually contain large quanti-ties of iron absorption inhibitors, particularly phytates and polyphenols. In addition recent observations sug-gest that diseases that affect the duodenum especially H. pylori infections and celiac disease may be more prevalent than previously suspected and that they may have an important contributory role. More research is needed to confirm these observations and to establish their possible relevance to the prevention of nutritional iron deficiency. Finally, diseases that cause blood loss, particularly hookworm infections, have an important contributory role leading to the high prevalence of iron deficiency in many developing countries.

2. Iron overload is far less prevalent than iron deficiency. Primary systemic iron overload (hemochromatosis) is almost always the result of an inherited abnormality of the regulation of iron transport that affects hepcidin or ferroportin. The common form of iron overload in Caucasians, HFE hemochromatosis, results from a relative hepcidin deficiency. Secondary iron overload occurs in thalassemia and sideroblastic anemia because the treatment of these conditions requires repeated blood transfusion and accelerated erythro-poiesis, which is characteristic of these disorders, reduces hepcidin expression.

3. The anemia of inflammation is characterized by decreased iron release from stores, reduced absorp-tion, low plasma iron and transferrin concentrations, restriction of the available iron supply for red blood cell production and mild or moderate anemia.

Increased hepcidin expression accounts for almost all the features of this condition which is generally con-sidered to be a host response that evolved to make iron less available to pathogens.

Major advances have been made in our understanding of the physiology of human iron metabolism and the patho-physiology of related disorders, although many questions still remain unanswered. Ongoing research in this field is required. The knowledge gained has nevertheless pro-vided a sound scientific foundation for approaches to combating nutritional iron deficiency.

FACTS:

• Humans normally have 40–50 mg iron/kg body weight.

• Approximately 75% of the iron in the body is present in metabolically active compounds; the remaining 25% constitutes a dynamic store that is turned over constantly.

• Iron delivery to the cells of the body is rigorously regulated by the control of absorption and release from stores.

• Hepcidin has a central role in controlling iron balance. • Iron deficiency, iron overload and the anemia of inflammation are the commonest disorders of iron metabolism. Nutritional iron deficiency results from a diet that contains insufficient bioavailable iron to meet requirements; primary iron overload is caused by inherited genetic mutations that lead to dysregula-tion of hepcidin or abnormalities in its receptor ferro-portin; the anemia of inflammation is the result of increased hepcidin expression induced by inflamma-tory cytokines.

7

OPTIMIZING THE BIOAVAILABILITY OF IRON COMPOUNDS FOR FOOD FORTIFICATION

Richard Hurrell and Ines Egli

In any fortification intervention it is critical to ensure the efficacy of the fortificants used. Bioavailability is of key importance in establishing efficacy. The bioavailability of iron compounds relative to ferrous sulphate (relative bioavailability value, RBV) has been proved useful in

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20 _{7 · Bioavailability of iron compounds for food fortification}

ranking their potential for food fortification. However, the efficacy of iron-fortified foods depends on the abso-lute absorption of the iron compound which is influenced by its RBV, but is also determined by the amount of fortificant added, the iron status of the consumer and the presence of either inhibitors (e.g. phytic acid) or enhancers (e.g. ascorbic acid) of iron absorption in the meal.

The World Health Organization (WHO) has published guidelines on food fortification, which include recommen-dations for preferred iron compounds and a procedure for defining iron fortification levels.

What iron compounds are recommended?

Although an order of preference for iron compounds is given by the WHO, it must be noted that preference also depends on the vehicle being used, and the guidelines list the most appropriate compounds to add to different vehicles: cereal flours, cereal-based foods, milk prod-ucts, cocoa prodprod-ucts, condiments. Each compound also has specific advantages and disadvantages that must be individually assessed.

Electrolytic iron is the only elemental iron powder re-commended. Atomized iron and carbon dioxide reduced iron powders are specifically not recommended due to their low RBV. Hydrogen-reduced iron and carbonyl iron powders may be recommended once there is more infor-mation on these compounds. In addition NaFeEDTA is not recommended for complementary food fortification as there are too few studies in young children and the Joint FAO/WHO Expert Committee on Food Additives has set limits in their recommendations.

How important is relative bioavailability (RBV)?

RBV is important for ranking different iron compounds relative to ferrous sulphate whose RBV is set at 100. The ranking is made either on the ability of the iron com-pound to replete hemoglobin in anemic rats or, more recently, to fractional iron absorption in humans using isotope techniques. As a result, four categories of iron compounds have been developed. Each category and each compound within the category has advantages and disadvantages that must be considered on an individual basis, based specifically on the selected fortification vehicle. Compounds’ characteristics can also vary depending on the method of manufacture, and their RBV may also be influenced by the food vehicle and the iron status of the subject, which can sometimes result in unexpectedly low RBV values.

• Category 1: Readily water-soluble and with an RBV of close to 100 in adults. Unfortunately these tend to cause unacceptable color and flavor changes. This category includes ferrous sulphate, ferrous gluconate, ferrous lactate and ferric ammonium citrate.

• Category 2: Poorly water-soluble but dissolve readily in the dilute acid of the gastric juice and so have a RBV of 100. These cause fewer organoleptic changes due to their low water solubility. This category includes ferrous fumarate and ferrous succinate. • Category 3: Insoluble in water and poorly soluble in

dilute acid so cause few if any sensory changes, but have lower and more variable RBV. This category includes ferric pyrophosphate, micronized dispersible ferric pyrophosphate (MDFP), ferric orthophosphate and elemental iron compounds.

• Category 4: The advantage of these compounds is that in the presence of phytic acid, they have an RBV 2–3 fold of that of ferrous sulphate. They are however more susceptible to adverse sensory changes than category 2 or 3 compounds. This category includes amino acid chelates, and NaFeEDTA.

How can one enhance bioavailability of fortification iron?

There are 5 key ways of enhancing the bioavailability of iron added to foods:

1. Ascorbic acid is the most commonly added com-pound for the enhancement of iron absorption but is sensitive to processing and storage losses. Ascorbic acid acts in a dose dependent way and the general recommendation is a 2:1 molar ratio of ascorbic acid to iron for low phytate products, and 4:1 for high phytate products.

2. Erythorbic acid is a stereoisomer of ascorbic acid and appears to have a better enhancing effect but is more sensitive to oxidation, which may limit its usefulness. 3. Organic acids, although they enhance iron absorption, are not an option (with the possible exception of fruit juices) as the large quantities required for the effect cause unacceptable flavor changes in most vehicles. 4. The EDTA complexes of Na₂EDTA and CaNa₂EDTA

are accepted food additives and could be used to enhance iron absorption of water-soluble iron com-pounds.

5. Degradation of phytic acid (a potent inhibitor of iron absorption) by the addition of exogenous phytases or by the activation of native phytases in cereal grains in an aqueous environment under con-trolled conditions of pH and temperature, might be appropriate in low cost cereal and legume based com-plementary foods.

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21

8 · Copper and zinc interactions in anemia

What levels of fortification are recommended?

Key when defining fortification levels is knowledge of the composition of the usual diet in order to estimate dietary iron bioavailability at 5%, 10% and 15%, and to have detailed information on the dietary intake of iron within the target population. The ultimate goal is to cal-culate the amount of extra daily nutrient required so that only 2.5% of the target population has an intake of below the Estimated Average Requirement (EAR). Care must also be taken when high levels of fortification are required to meet the goal, to ensure that other population groups do not exceed the upper limits.

It is noted that the EAR cut point method should not be used to estimate prevalence of inadequate iron intakes as iron intakes of some population subgroups (e.g. men-struating women and children) are not normally distrib-uted. In these population groups it is recommended to use the full probability approach to define the fortifica-tion level. The WHO provides probability tables for this.

Technically we now know how to design an efficacious iron fortified food. This information is provided in the WHO Guidelines. When designing an iron-fortified food, the food manufacturer must choose the iron com-pound with the highest RBV which causes no/limited sensory changes in the food and which is cost effective. At the same time, the level of fortification should be based on the needs and eating habits of the consumer. Widespread infections and concurrent deficiencies in other micronutrients may blunt its efficacy. In addition, it must not be forgotten that an efficient manufacturing and distribution system, quality control, monitoring proce-dures, synergistic health measures and good social mar-keting must also be in place for any intervention to be successful.

8

COPPER AND ZINC INTERACTIONS IN ANEMIA: A PUBLIC HEALTH PERSPECTIVE

Manuel Olivares, Eva Hertrampf and Ricardo Uauy

Both copper and zinc are essential nutrients and deficien-cies of both result in anemia. Experimental studies have shown an inhibitory effect of zinc on iron absorption and

it has been proposed that they compete for a shared absorptive pathway, but the exact mechanisms involved in the interaction at the absorption level are not fully understood. It has also been demonstrated that large doses of zinc inhibit copper absorption and may produce copper deficit, which indirectly could affect iron status leading to anemia. Zinc and copper have an antagonistic interaction within the erythrocyte. The public health relevance of these interactions has been considered lim-ited in the past, but recent studies show that combined iron and zinc supplementation was less efficacious than single supplementation with iron in reducing the preva-lence of anemia and in improving iron status. It should be noted that some studies have not confirmed this poten-tially detrimental effect but three studies in subjects pre-sumably deficient in iron and zinc, demonstrated a larger increase in hemoglobin after combined iron and zinc sup-plementation than with iron or zinc supsup-plementation alone.

In the developing world iron deficiency coexists with micronutrient deficiencies and infection, and recent research shows that copper and zinc deficiencies could be a contributing factor in the increased frequency of infections. In addition, acute infections are a well-recog-nized cause of mild to moderate anemia. Resistance to infections depends on a healthy immune function and copper and zinc are both necessary for the normal func-tion of the immune system. In addifunc-tion to alterafunc-tions to the immune system, zinc deficiency may also contribute to an increased susceptibility to pathogens and several studies have shown an increased incidence of diarrhea and acute lower respiratory infection in zinc deficiency. It has also been found that zinc supplementation may reduce the incidence of malaria. However, an immuno-suppressive effect has been observed at very high doses of supplemental zinc, but this might be explained in part by secondary copper deficiency induced by excessive zinc. Neutropenia is a frequent clinical manifestation of copper deficiency and this may be the link between an increased frequency of severe lower respiratory infec-tions that have been described in copper deficient infants.

The modification of laboratory indices of iron status are related to the severity of the infectious process. This know-ledge has led to the use of serum transferring receptor as an aid in the interpretation of iron status in populations with a high frequency of infections.

What are the basics of copper metabolism?

Copper is an essential nutrient which is absorbed primarily in the duodenum by a mechanism not yet fully understood,

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22 _{9 · Nutritional anemia: B-vitamins}

but the chemical form of the copper in the lumen markedly affects its absorption. Apparent absorption varies from 15–80% (usual range 40–60%) and is determined by host and dietary related factors (intake and nutritional status), some of which have yet to be defined. As solubility of the compound increases, copper is absorbed more effectively and it seems that animal protein, human milk and histidine enhance absorption whereas cows milk, zinc, ascorbic acid and phytates diminish absorption.

Copper deficiency is usually the consequence of low copper stores at birth; inadequate dietary copper intake; poor absorption and increased requirements induced by rapid growth or increased copper losses and is often as a result of multiple factors. Acquired copper deficiency is a clinical syndrome occurring mainly in infants, and is more frequent in preterm infants (especially of a very low birth weight) and infants fed exclusively cow’s milk based diets and should be suspected in infants with pro-longed or recurrent diarrheal episodes. It would seem that the most common cause of overt, clinical copper deficiency is insufficient copper supply during the nutri-tional recovery of malnourished children. High oral intakes of zinc and iron decrease copper absorption and could predispose to deficiency. Common clinical mani-festations are anemia (92%), neutropenia (84%) and bone abnormalities. The hematological changes are attributed to a number of mechanisms and are fully reversed by copper supplementation but are unresponsive to iron therapy alone.

Dietary copper deficit and genetic defects of copper metabolism have significant effects on iron metabolism and red cell resistance to oxidative stress, and thus may contribute to the burden of anemia. In addition, copper is also associated with impaired host defenses and could increase the burden of anemia secondary to infection. Copper deficit should be included in the differential diag-nosis of anemia unresponsive to iron supplementation. Copper excess may also contribute to anemia by induc-ing hemolysis.

What are the basics of zinc metabolism?

Zinc is widely found within cells, which makes the study of zinc dependent mechanisms to determine physiolog-ical function difficult, but zinc plays a central role in cellular growth, differentiation and metabolism. Some of the critical functions affected by zinc status include preg-nancy outcome, fetal growth and development, linear growth, susceptibility to infection and neurobehavioral development. Zinc is absorbed through the small intes-tines and is affected by its chemical form and the

pres-ence of inhibitors or enhancers and adapts to physiolog-ical need. The total body zinc content is 1.5–2.5g and is determined by diet content, zinc nutritional status and zinc bioavailability from food. The main causes of zinc deficiency are low intake, increased requirements, mal-absorption, increased losses and impaired utilization. The first descriptions of severely zinc deficient subjects included anemia, but this could possibly be due to com-bined iron deficiency or the special effect of zinc on red cell maturation. The mechanism of altering erythro-poiesis is not fully understood.

Zinc deficit may contribute to the burden of anemia by altering erythropoiesis and decreasing red cell resistance to oxidative stress, impairing host defense. In addition, high doses of zinc supplementation interfere with copper and iron absorption and may also interfere with iron mobilization and impaired immune responses.

Although the potential public health relevance of zinc and copper interactions with iron remains undefined, they both potentially impact on the burden of anemia, directly and indirectly through infection, and must not be ignored in nutritional anemia interventions.

9

NUTRITIONAL ANEMIA – B VITAMINS

John Scott

Although most anemia in developing countries is due to iron deficiency, a proportion may be due to deficiency of vitamins of B complex, principally folate and vitamin B₁₂. This anemia is macrocytic but with the presence of abnormal red cell precursors in the bone marrow called megaloblasts. Concurrent presence of iron deficiency results in an anemia that is often normocytic. This can result in diagnostic difficulties and as a result, what is often attrib-uted to pure iron deficiency may frequently be due in part to folate or vitamin B₁₂deficiency, and the true prevalence of folate of vitamin B₁₂deficiency is difficult to establish.

Some nutrients are not at risk of being deficient because of their adequate level in most diets. Others are of particular risk in certain individuals and under certain conditions. For the B complex vitamins, there is a wide spectrum